During inflammation, immune cells migrate into inflamed tissue and release opioid peptides that activate opioid receptors on peripheral sensory neurons to reduce pain. A characteristic of the inflamed environment in which these opioids act is acidic pH. Activation of opioid receptors leads to a decrease in the calcium component of neuronal action potentials. We investigated the hypothesis that inhibitory effects of opioids on intracellular calcium transients in dorsal root ganglion neuronal cultures are potentiated at acidic extracellular pH. Intracellular calcium responses to stimulation with capsaicin were measured in untreated neurons or after preincubation with beta-endorphin or morphine. beta-Endorphin significantly inhibited calcium responses to 300 nmol/L capsaicin at the lowest experimental extracellular pH (6.1, 6.5, and 7.2), whereas morphine inhibited capsaicin (300 nmol/L) responses significantly at pH 6.1 with a trend of inhibition at pH 6.5. The effect of pH on morphine inhibition of K+ -evoked calcium responses was also assessed. Morphine inhibition of calcium responses was significantly enhanced at pH 6.8 compared with pH 7.2 and pH 7.6. The inhibitory effects were reversed by naloxone, an opioid receptor antagonist. In conclusion, low extracellular pH potentiated beta-endorphin and morphine inhibition of calcium transients and might contribute to improved opioid efficacy during inflammation.
Perspective: The results of the current study suggest that acidic pH might contribute to increased opioid efficacy in inflamed tissue. This highlights the therapeutic potential of endogenous opioid analgesia, whereby opioid peptides are delivered locally in inflamed tissues, as well as the use of locally applied opioids in inflammatory conditions.